Loss of long term protection with the inclusion of HIV pol to a DNA vaccine encoding gag

Garrod, Tamsin; Gargett, Tessa; Yu, Wenbo; Major, Lee; Burrell, Christopher J.; Wesselingh, Steven; Suhrbier, Andreas; Grubor‐Bauk, Branka; Gowans, Eric J.

doi:10.1016/j.virusres.2014.08.008

Cited by 6 publications

(11 citation statements)

References 40 publications

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“…Multiple efforts made by us, and by others, to enhance the immunogenicity of HIV-1 RT had limited success [12–14, 16–18]. Recently, we discovered that both the wild-type and drug-resistant RT variants induce oxidative stress in the expressing cells [19].…”

Section: Discussionmentioning

confidence: 99%

“…A recent study by Garrod et al compared the performance in C57BL/6 mice of DNA vaccines encoding single HIV antigens in combination with HIV gag- and pol-based DNA immunogens. The efficacy of vaccination was tested by challenge with a chimeric EcoHIV virus that can infect mice [14]. At 60 days, there was significantly lower frequency of induced antigen-specific CD8( + ) T cells in the spleens of pCMVgag-pol-vaccinated mice compared with mice immunized with single pCMVgag.…”

Section: Introductionmentioning

confidence: 99%

“…At 60 days, there was significantly lower frequency of induced antigen-specific CD8( + ) T cells in the spleens of pCMVgag-pol-vaccinated mice compared with mice immunized with single pCMVgag. Furthermore, while short-term viral control of EcoHIV was similar for gag- and gag-pol DNA-vaccinated mice, only gag DNA-vaccinated ones were able to control EcoHIV two months postvaccination, indicating that inclusion of the HIV pol gene may reduce the durable control over viral replication [14]. …”

Section: Introductionmentioning

confidence: 99%

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Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice

Latanova

Petkov

Kuzmenko

et al. 2017

Journal of Immunology Research

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Reverse transcriptase (RT) is a key enzyme in viral replication and susceptibility to ART and a crucial target of immunotherapy against drug-resistant HIV-1. RT induces oxidative stress which undermines the attempts to make it immunogenic. We hypothesized that artificial secretion may reduce the stress and make RT more immunogenic. Inactivated multidrug-resistant RT (RT1.14opt-in) was N-terminally fused to the signal providing secretion of NS1 protein of TBEV (Ld) generating optimized inactivated Ld-carrying enzyme RT1.14oil. Promotion of secretion prohibited proteasomal degradation increasing the half-life and content of RT1.14oil in cells and cell culture medium, drastically reduced the residual polymerase activity, and downmodulated oxidative stress. BALB/c mice were DNA-immunized with RT1.14opt-in or parental RT1.14oil by intradermal injections with electroporation. Fluorospot and ELISA tests revealed that RT1.14opt-in and RT1.14oil induced IFN-γ/IL-2, RT1.14opt-in induced granzyme B, and RT1.14oil induced perforin production. Perforin secretion correlated with coproduction of IFN-γ and IL-2 (R = 0,97). Both DNA immunogens induced strong anti-RT antibody response. Ld peptide was not immunogenic. Thus, Ld-driven secretion inferred little change to RT performance in DNA immunization. Positive outcome was the abrogation of polymerase activity increasing safety of RT-based DNA vaccines. Identification of the molecular determinants of low cellular immunogenicity of RT requires further studies.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice

Latanova

Petkov

Kuzmenko

et al. 2017

Journal of Immunology Research

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show abstract

“…Vaccinated mice were challenged via the intra-peritoneal (IP) route with EcoHIV equivalent to 1.5 μg p24, then spleen, blood and peritoneal exudate cells (PECs) collected 7 days post challenge and examined by qRT-PCR as described previously2458. Results were normalised to RPL13a mRNA levels after examining primer efficiency using the ΔΔCT (threshold cycle) quantification method59.…”

Section: Methodsmentioning

confidence: 99%

Mucosal vaccination with a live recombinant rhinovirus followed by intradermal DNA administration elicits potent and protective HIV-specific immune responses

Tomusange

Wijesundara

Gummow

et al. 2016

Sci Rep

Self Cite

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Mucosal immunity is deemed crucial to control sexual transmission of human immunodeficiency virus (HIV). Herein we report the efficacy of a mucosal HIV vaccine strategy comprising intranasal (IN) vaccination with a cocktail of live recombinant human rhinoviruses (HRVs) encoding overlapping fragments of HIV Gag and full length Tat (rHRV-Gag/Tat) followed by intradermal (ID) vaccination with DNA vaccines encoding HIV Gag and Tat (pVAX-Gag-Tat). This heterologous prime-boost strategy will be referred to hereafter as rHRV-DNA. As a control, IN vaccination with wild type (wt)-HRV-A1 followed by a single ID dose of pVAX (wt-HRV-A1/pVAX vaccination) was included. rHRV-DNA vaccination elicited superior multi-functional CD8+T cell responses in lymphocytes harvested from mesenteric lymph nodes and spleens, and higher titres of Tat-specific antibodies in blood and vaginal lavages, and reduced the viral load more effectively after challenge with EcoHIV, a murine HIV challenge model, in peritoneal macrophages, splenocytes and blood compared compared with wt-HRV-A1/pVAX vaccination or administration of 3 ID doses of pVAX-Gag-Tat (3X pVAX-Gag-Tat vaccination). These data provide the first evidence that a rHRV-DNA vaccination regimen can induce HIV-specific immune responses in the gut, vaginal mucosa and systemically, and supports further testing of this regimen in the development of an effective mucosally-targeted HIV-1 vaccine.

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“…For example, newly designed vaccines against HIV are intended to specifically activate HIV-specific CD8 + T cells 8 . However, to date, CD8 + T cell–mediated vaccines have failed to protect the host from persistent infection 9 . Therefore, the role of vaccine-induced virus-specific CD8 + T cells in long-term protection is still being debated 10 11 12 .…”

mentioning

confidence: 99%

Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8+ T-cell priming and viral control

Duhan

Khairnar

Friedrich

et al. 2016

Sci Rep

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Clinically used human vaccination aims to induce specific antibodies that can guarantee long-term protection against a pathogen. The reasons that other immune components often fail to induce protective immunity are still debated. Recently we found that enforced viral replication in secondary lymphoid organs is essential for immune activation. In this study we used the lymphocytic choriomeningitis virus (LCMV) to determine whether enforced virus replication occurs in the presence of virus-specific antibodies or virus-specific CD8+ T cells. We found that after systemic recall infection with LCMV-WE the presence of virus-specific antibodies allowed intracellular replication of virus in the marginal zone of spleen. In contrast, specific antibodies limited viral replication in liver, lung, and kidney. Upon recall infection with the persistent virus strain LCMV-Docile, viral replication in spleen was essential for the priming of CD8+ T cells and for viral control. In contrast to specific antibodies, memory CD8+ T cells inhibited viral replication in marginal zone but failed to protect mice from persistent viral infection. We conclude that virus-specific antibodies limit viral infection in peripheral organs but still allow replication of LCMV in the marginal zone, a mechanism that allows immune boosting during recall infection and thereby guarantees control of persistent virus.

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Loss of long term protection with the inclusion of HIV pol to a DNA vaccine encoding gag

Cited by 6 publications

References 40 publications

Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice

Fusion to Flaviviral Leader Peptide Targets HIV-1 Reverse Transcriptase for Secretion and Reduces Its Enzymatic Activity and Ability to Induce Oxidative Stress but Has No Major Effects on Its Immunogenic Performance in DNA-Immunized Mice

Mucosal vaccination with a live recombinant rhinovirus followed by intradermal DNA administration elicits potent and protective HIV-specific immune responses

Virus-specific antibodies allow viral replication in the marginal zone, thereby promoting CD8+ T-cell priming and viral control

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